The invention relates to reducing hair growth in mammals, particularly for cosmetic purposes.
A main function of mammalian hair is to provide environmental protection. However, that function has largely been lost in humans, in whom hair is kept or removed from various parts of the body essentially for cosmetic reasons. For example, it is generally preferred to have hair on the scalp but not on the face.
Various procedures have been employed to remove unwanted hair, including shaving, electrolysis, depilatory creams or lotions, waxing, plucking, and therapeutic antiandrogens. These conventional procedures generally have drawbacks associated with them. Shaving, for instance, can cause nicks and cuts, and can leave a perception of an increase in the rate of hair regrowth. Shaving also can leave an undesirable stubble. Electrolysis, on the other hand, can keep a treated area free of hair for prolonged periods of time, but can be expensive, painful, and sometimes leaves scarring. Depilatory creams, though very effective, typically are not recommended for frequent use due to their high irritancy potential. Waxing and plucking can cause pain, discomfort, and poor removal of short hair. Finally, antiandrogensxe2x80x94which have been used to treat female hirsutismxe2x80x94can have unwanted side effects.
It has previously been disclosed that the rate and character of hair growth can be altered by applying to the skin inhibitors of certain enzymes. These inhibitors include inhibitors of 5-alpha reductase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, gamma-glutamyl transpeptidase, and transglutaminase. See, for example, Breuer et al., U.S. Pat. No. 4,885,289; Shander, U.S. Pat. No. 4,720,489; Ahluwalia, U.S. Pat. No. 5,095,007; Ahluwalia et al., U.S. Pat. No. 5,096,911; and Shander et al., U.S. Pat. No. 5,132,293.
xcex1-Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), a rate-limiting enzyme in the de novo biosynthesis of putrescine, spermidine, and spermine. The role of these polyamines in cellular proliferation is not yet well understood. However, they seem to play a role in the synthesis and/or regulation of DNA, RNA and proteins. High levels of ODC and polyamines are found in cancer and other cell types that have high proliferation rates.
DFMO binds the ODC active site as a substrate. The bound DFMO is then decarboxylated and converted to a reactive intermediate that forms a covalent bond with the enzyme, thus preventing the natural substrate ornithine from binding to the enzyme. Cellular inhibition of ODC by DFMO causes a marked reduction in putrescine and spermidine and a variable reduction in spermine, depending on the length of treatment and the cell type. Generally, in order for DFMO to cause significant antiproliferative effects, the inhibition of polyamine synthesis must be maintained by continuous inhibitory levels of DFMO because the half-life of ODC is about 30 min, one of the shortest of all known enzymes.
A skin preparation containing DFMO (sold under the name Vaniqa(copyright) by Bristol Myers Squibb), has recently been approved by the Food and Drug Administration (FDA) for the treatment of unwanted facial hair growth in women. Its topical administration in a cream based vehicle has been shown to reduce the rate of facial hair growth in women. Vaniqa(copyright) facial cream includes a racemic mixture of the xe2x80x9cD-xe2x80x9d and xe2x80x9cL-xe2x80x9d enantiomers of DFMO (i.e., D, L-DFMO) in the monohydrochloride form at a concentration of 13.9% by weight active (15%, as monohydrochloride monohydrate). The recommended treatment regimen for Vaniqa(copyright) is twice daily. The cream base vehicle in Vaniqa(copyright) is set out in Example 1 of U.S. Pat. No. 5,648,394, which is incorporated herein by reference.
It generally takes about eight weeks of continuous treatment before the hair growth-inhibiting efficacy of Vaniqa(copyright) cream becomes apparent. Vaniqa(copyright) cream has been shown to decrease hair growth an average of 47%. In one study, clinical successes were observed in 35% of women treated with Vaniqa(copyright) cream. These women exhibited marked improvement or complete clearance of their condition as judged by physicians scoring a decrease in visibility of facial hair and a decrease in skin darkening caused by hair. Another 35% of the women tested experienced some improvement in their condition. However, there were some women who exhibited little or no response to treatment.
Accordingly, although Vaniqa(copyright) cream is an effective product, it would be even more effective if it provided an earlier onset of hair growth inhibition (i.e., exhibited efficacy earlier than eight weeks) and/or exhibited an increased clinical success rate (i.e., exhibited efficacy in a greater percentage of users). Such improved results cannot be obtained by simply increasing the concentration of D, L-DFMO in the cream vehicle. First, increasing the concentration of D, L-DFMO above about 14% can cause increased stinging of the skin and/or can leave a residue, making it aesthetically unacceptable. Second, it is difficult to formulate compositions with an active concentration above about 15% because significantly higher concentrations of D,L-DFMO are not adequately soluble in the vehicle or destabilize the emulsion.
Molecules that are identical to each other in chemical structural formula and yet are not superimposable upon each other are enantiomers. In terms of their physiochemical properties enantiomers differ only in their ability to rotate the plane of plane-polarized light, and this property is frequently used in their designation. Those entiomers that rotate plane-polarized light to the right are termed dextrorotatory, indicated by either a (+)- or d- or D- before the name of the compound; those that rotate light to the left are termed laevorotatory indicated by a (xe2x88x92)- or 1- or L- prefix. A racemic mixture is indicated by either a (xc2x1)- or d,1- or D,L- prefix. By another convention (or nomenclature), the R,S or the sequence rule can be used to differentiate enantiomers based on their absolute configuration. Using this system the L-DFMO corresponds to the R-DFMO, and the D-DFMO corresponds to the S-DFMO. Enantiomers are physiochemically similar in that they have similar melting points, boiling points, relative solubility, and chemical reactivity in an achiral environment. A racemate is a composite of equal molar quantities of two enantiomeric species, often referred to as the DL-form. Individual enantiomers of chiral molecules may possess different pharmacological profiles, i.e., differences in pharmacokinetics, toxicity, efficacy, etc.
The present invention provides a method (typically a cosmetic method) of reducing unwanted human hair growth by applying to the skin a dermatologically acceptable topical composition comprising xcex1-difluoromethylornithine (DFMO) in an amount effective to reduce hair growth, wherein the xcex1-difluoromethylornithine comprises at least about 70% by weight of L-xcex1-difluoromethylornithine (L-DFMO). The unwanted hair growth may be undesirable from a cosmetic standpoint or may result, for example, from a disease or an abnormal condition (e.g., hirsutism). Preferably the DFMO will comprise at least about 80%, more preferably at least about 90%, most preferably at least about 95% of the L-DFMO. Ideally, the DFMO will be substantially optically pure L-DFMO. xe2x80x9cSubstantially optically purexe2x80x9d means that the DFMO comprises at least 98% L-DFMO. xe2x80x9cOptically purexe2x80x9d L-DFMO means that the DFMO comprises essentially 100% L-DFMO. DFMO, as used herein, includes DFMO itself and pharmaceutically acceptable salts thereof.
The present invention also relates to topical compositions comprising a dermatologically or cosmetically acceptable vehicle and xcex1-difluoromethylornithine (DFMO) in an amount effective to reduce hair growth, wherein the xcex1-difluoromethylornithine comprises at least about 70% by weight of L-xcex1-difluoromethylornithine (L-DFMO). In addition, the present invention relates to the use of xcex1-difluoromethylornithine for the manufacture of a therapeutic topical composition for reducing hair growth, wherein the xcex1-difluoromethylornithine comprises at least about 70% by weight of L-xcex1-difluoromethylornithine (L-DFMO).
The above compositions containing a preponderance of L-DFMO have an enhanced efficacy relative to similar compositions containing racemic D,L-DFMO. This enhanced efficacy can manifest itself, for example, in earlier onset of hair growth inhibiting activity, greater reduction of hair growth rate, and/or greater number of subjects demonstrating reduced hair growth. As a result, a composition using the same vehicle as Vaniqa(copyright) cream, but including about 10%-15% by weight of, for example, substantially optically pure L-DFMO, is more effective, in terms of onset of efficacy and rate of clinical success than Vaniqa(copyright) cream. Preferred compositions include about 0.1% to about 30%, preferably about 1% to about 20%, more preferably about 5% to about 15%, by weight of the DFMO, as described above, and produce less stinging than Vaniqa(copyright) cream.
Some preferred compositions (1) provide an average inhibition of at least 35%, more preferably at least 40%, when tested at a DFMO concentration of 0.3% in the Golden Syrian Hamster assay; (2) exhibit efficacy in at least 60%, more preferably at least 70%, most preferably at least 80% of Golden Syrian Hamsters, when tested at a DFMO concentration of 2% in the Golden Syrian Hamster Assay; (3) exhibit maximal efficacy in at least 40%, more preferably at least 50%, most preferably at least 55% of Golden Syrian Hamsters, of the time when tested at a DFMO concentration of 2% in the Golden Syrian Hamster assay; (4) provide an average inhibition of hair growth of at least 15%, more preferably at least 20%, most preferably at least 25%, when tested at a DFMO concentration of 1% in the twice a week Golden Syrian Hamster assay; (5) provide an average reduction of hair follicle spatial mass of at least 35%, more preferably at least 45%, most preferably at least 50%, when tested at a DFMO concentration of 0.5% in the Golden Syrian Hamster hair follicle mass assay; and/or (6) provide an average reduction of hair follicle density of at least 20%, more preferably at least 30%, most preferably at least 35%, when tested at an DFMO concentration of 0.5% in the Golden Syrian Hamster hair follicle density assay. The DFMO also preferably includes sufficient L-DFMO to provide a hair follicle growth inhibition of at least 15%, more preferably at least 25%, most preferably at least 30%, when tested in the Human Hair Follicle Growth assay at a concentration of 0.5 mM. These assays will be described in detail below. A xe2x80x9cDFMO concentration ofxe2x80x9d, when used in connection with these assays means that prior to testing the composition in an assay the amount of DFMO used in the composition has been adjusted to provide the concentration listed for the assay, with corresponding adjustments to the other components of the composition.
Preferred compositions of the present invention provide (1) significantly earlier onset (e.g., less than six weeks, preferably less than four weeks) of reduced facial hair growth than Vaniqa(copyright) cream in women when applied twice daily; (2) a substantial reduction (as exhibited by marked improvement or complete clearance) of facial hair in at least 50% of women when applied twice a day or less frequently; (3) a substantially complete clearance of facial hair in at least 25% of women when applied twice a day or less frequently; (4) at least approximately the same efficacy of Vaniqa(copyright) cream (when the Vaniqa(copyright) cream is applied twice a day) when applied once a day to facial area in women.
Other features and advantages of the invention will be apparent from the description and the claims which follow.
The preferred composition includes substantially optically pure L-DFMO or DFMO including a preponderance of L-DFMO in a cosmetically and/or dermatologically acceptable vehicle. The composition may be a solid, semi-solid, or liquid. The composition may be, for example, a cosmetic and dermatologic product in the form of an, for example, ointment, lotion, foam, cream, gel, or solution. The composition may also be in the form of a shaving preparation or an aftershave. The vehicle itself can be inert or it can possess cosmetic, physiological and/or pharmaceutical benefits of its own.
The composition may include one or more other types of hair growth reducing agents, such as those described in U.S. Pat. No. 5,364,885 or U.S. Pat. No. 5,652,273.
The concentration of DFMO in the composition may be varied over a wide range up to a saturated solution, preferably from 0.1% to 30% by weight; the reduction of hair growth increases as the amount of DFMO applied increases per unit area of skin. The maximum amount effectively applied is limited only by the rate at which the DFMO penetrates the skin. The effective amounts may range, for example, from 10 to 3000 micrograms or more per square centimeter of skin.
Vehicles can be formulated with liquid or solid emollients, solvents, thickeners, humectants and/or powders. Emollients include, for example, stearyl alcohol, mink oil, cetyl alcohol, oleyl alcohol, isopropyl laurate, polyethylene glycol, olive oil, petroleum jelly, palmitic acid, oleic acid, and myristyl myristate. Solvents include, for example, water, ethyl alcohol, isopropanol, acetone, diethylene glycol, ethylene glycol, dimethyl sulfoxide, and dimethyl formamide. A preferred vehicle for compositions of the present invention is described in U.S. Pat. No. 5,648,394.
The composition also may include components that enhance the penetration of the compound into the skin and/or to the site of action. Examples of penetration enhancers include urea, polyoxyethylene ethers (e.g., Brij-derivatives), terpenes (e.g., nerolidol or 3-hydroxy-3,7,11-trimethyl-1,6,10-dodecatriene), cis-fatty acids (e.g., oleic acid, palmitoleic acid), acetone, laurocapram, dimethyl sulfoxide, 2-pyrrolidone, oleyl alcohol, glyceryl-3-stearate, propan-2-ol, myristic acid isopropyl ester, and propylene glycol.
The composition also can be formulated to provide a reservoir within or on the surface of the skin to provide for a continual slow release of the DFMO. The composition also may be formulated to evaporate slowly from the skin, allowing the inhibitor extra time to penetrate the skin.
Optically pure L-DFMO and optically pure D-DFMO can be prepared by known methods. See, for example, U.S. Pat. No. 4,309,442, Gao et al., Ann. Pharm. Fr. 52(4):184-203 (1994); Gao et al., Ann. Pharm. Fr. 52(5):248-59 (1994); and Jacques et al., Tetrahedron Letters, 48:4617 (1971), all of which are incorporated by reference herein.
The following are examples of compositions.